Management and Outcomes of Anti-CD38 Refractory Patients: The Impact of Retreatment and of Subsequent Therapies

he development of resistance to therapy remains the main barrier to cure myeloma, and most patients develop disease that is refractory to treatments, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and monoclonal antibodies targeting CD38. CD38-based therapy has become a backbone therapy across all lines, 1 but, more patients will be refractory to these drugs at early lines and management of relapsed/refractory multiple myeloma (RRMM) that is refractory to anti-CD38 therapies is challenging despite the increasing number of new options (anti-body-drug conjugated antibodies, bispecific antibodies 2 and CAR-T cell therapies 3–5 ). In clinical practice, the management of such patients is based either in the use of drugs with new mechanisms of action (if available) or in the retreatment with previously used agents. Previous studies have described the poor prognosis of such patients but may differ from todays’ real-world patients. 6,7 In addition, the outcomes of RRMM refractory to CD38 may have changed with the use of anti-CD38 containing triplets in earlier lines rather than anti-CD38 mono-therapy later. Such data are of clinical relevance since they

and penta-refractory status were based on previously published definitions. 6The analysis was based on data from the prospectively maintained Department's database and assessed for disease response and progression according to standard institutional protocol, using standard International Myeloma Working Group (IMWG) criteria to evaluate response and progression. 8n approval by the Institutional Ethics Committee/Scientific Council was obtained for access to anonymized data, analysis, and publication.This is an observational study and there was no primary hypothesis testing; P-values are exploratory.Progression free survival (PFS) for the line of therapy post-CD38 failure was calculated from the date of start of this therapy until progression, death or last follow-up date.Duration of response (DoR) was calculated for responding patients (≥partial response [PR]), from the date of first response (≥PR) to the date of progression, death or last follow up.OS post anti-CD38 failure was defined as the time from the start of subsequent line of therapy until date of death or of last follow up.
The above results confirm that patients failing anti-CD38 therapy have poor prognosis.However, the median DoR was 11.8 months and a group of patients, such as those with previously long-maintained responses to anti-CD38 could achieve quite long DOR (median 26.7 months); this data sets benchmarks for the evaluation of new treatments in this setting and the interpretation of results of recent trials.Although this is not the first study to explore outcomes of patients refractory to anti-CD38-based therapy, 6,7 it has differences from previously published cohorts and provides a more contemporary view.Compared to the MAMMOTH study 6 our patients had fewer prior lines (4 versus 3), indicating earlier exposure to anti-CD38 therapy, closer to current real-world paradigm where daratumumab and isatuximab combinations have been approved for use in early lines.All our patients received therapy after T 0 , and 15% received belantamab mafodotin, 5% Selinexor-based regimens, and 23% triplet CD38-containing regimens.Compared to LocoMMotion study, 7 there are differences in the number of prior lines (4 versus 3), with no significant difference in rates of triple-class and penta-refractory patients (73.8% and 17.7%, respectively) but, in the LocoMMotion study the ORR at the standard of care regimens that were used was 29.8%, the median PFS was 4.6 and the median OS 12.4 months.Our patient population is not significantly different from the KarMMa-3 study cohort (median 3 prior lines), although patients in that study were younger (median 63 versus 68 years), and fitter. 5The median PFS in the SoC arm of KarMMa-3 was 4.4 months, with 38% of patients treated with daratumumab-based combinations (versus 23% in our study).Thus, our data could serve as benchmarks for comparisons with emerging therapies, using indirect approaches.However, our data come from a single-center cohort which may hamper definite conclusions, not being representative of other practices.
Recycling previous therapies, in different combinations, is a bridging strategy that offered prolonged remissions only in a minority of patients [9][10][11] ; new treatment approaches and strategies should be prioritized for patients failing anti-CD38.The DoR to prior CD38-targeting therapy was prognostic for the outcomes on subsequent CD38-based combinations therapy; a similar observation for the duration of prior response to IMiD when switching from lenalidomide to pomalidomide has also been reported by our group 12 and others. 13The cutoff of 12 months for the duration of PFS to index anti-CD38, could be cohort-specific and may differ in different cohorts.Since the cutoff date of this study, treatment options have significantly evolved (bispecific antibodies 2 and chimeric antigen receptor T cells [3][4][5] ), but the evaluation of their impact will need further real-world studies, as they were not available at that time; in the context of availability of these options, our study may have a time bias.Nonetheless, our data in combination with data from the previous studies indicate that refractoriness to anti-CD38-based therapy is a critical point in the natural history of the disease.Notably, there were no significant differences in the PFS post-CD38 failure for those who were triple-class or penta-refractory versus those who were refractory to anti-CD38 plus one more drug.The underlying biology of refractoriness to CD38-targeting therapy is not well understood but may involve both the clone and the immune micro-and macro-environment.

Figure 1 .
Figure 1.Outcomes of patients after failure of anti-CD38 therapy.(A) PFS in the line of therapy post-anti-CD38 failure and (B) OS after anti-CD38 failure, for non-triple-class refractory, triple-class refractory, and penta-refractory patients (C) PFS in the line of therapy post-anti-CD38 failure and (D) OS after anti-CD38 failure for patients who had duration of PFS in the index anti-CD38-based therapy that lasted more or less than 12 months.OS = overall survival; PFS = progression free survival.

Table 1
Characteristic of the Patients at T 0 and Relevant PFS and OS After T 0 With 95% CI